Docetaxel (docetaxel, Docetaxel, C43HS3NO14) is based on the structure of a natural anticancer drug taxol, which is a novel anticancer drugs obtained after structural modification. The resistance spectrum of docetaxel and paclitaxel are similar. The mechanism of docetaxel is to promote tubulin polymerization and prevent microtubule depolymerization, thereby the mitosis and proliferation of the cancer cell is to be inhibited, and the efficacy of docetaxel is better than that of paclitaxel.
In vitro studies show that the cell lines in the human breast, colon, bladder, and epithelial with IC50 is less than 9 times paclitaxel. In vivo studies suggest that docetaxel has a high degree of anti-tumor activity, after treatment and transplanted tumors in mice; murine tumor can be completely dissipated. More importantly, docetaxel to paclitaxel-resistant cell line does not spontaneously produce docetaxel cross-resistance.
Docetaxel is white or almost white powder which is a drug with highly fat-soluble and insoluble in water. The solubility of docetaxel in water is 6-7 μg/ml. In order to increase the solubility of docetaxel, the currently commercial formulation of docetaxel are required to add Tween-80 as a surfactant. The use of Tween 80 has two major drawbacks.
The first drawback is that the strong adverse reaction is brought to patients. Tween-80 may cause adverse reaction that includes allergic reactions, hemolysis, cardiovascular adverse reactions and fluid retention. The publication document has been published such as Tween-80 cause allergic reactions animal preliminary exploration, Toxicology 2007, 04, and Pharmacology, pharmacokinetics Research and Analysis Methods 80 pharmaceutical excipients Twain, Chinese medicine thing, 2008, Vol. 22, No. 8. Therefore, the patients need to the oral glucocorticoids drug desensitization in advance. Accordingly, an allergies reaction has been occurred in patients that need to injection of epinephrine, which will undoubtedly increase the burden on patients.
The second drawback is that the administration method is more complex, more difficult to use. Take Taxotere as an example, the concentration drug is mixed with the dilution to prepare the pre-mixed solution, and then the pre-mixed solution is diluted with 0.9% physiological saline solution to prepare the pre-mixed dilution. Within 4 hours, the pre-mixed dilution is infused for 1 hour. In infusion process, the concentration drug mixed with the dilution requires to upside down carefully about 45 seconds but did not require stirring. The bubbles might be generated in the resulted solution, such that the resulted solution is standing for 5 minutes to discharge the bubbles. The docetaxel injection product, Docetaxel, is produced by Qilu pharmaceutical production. The specification has the following caption: “the labeled amount of each bottle is 1 ml: 20 mg of docetaxel; the actual docetaxel solution is filled with 1.2 ml of 20 mg/ml, equivalent to 24 mg of docetaxel. This volume is used for the supplement for the volume lost due to the viscous liquid is adhered on the bottle wall, and the amount of the liquid cannot be withdrawn from the bottle which is called “dead volume”. During operation, a syringe extracts docetaxel from the bottle and dilutes to 5% glucose injection solution or 0.9% sodium chloride injection solution. In order to avoid the drug overdose toxicity, the vial and syringe cannot be rinsed by solvent
The polymer micelle with nanoscale particle size is a core-shell structure which is spontaneously formed by amphiphilic block copolymers. The polymer micelle is used as an administration carrier that is firstly proposed by Bader et al in 1984. The amphiphilic block copolymer encapsulated the drug within a hydrophobic core of the polymer micelle to achieve the solubility of insoluble drugs and further improve the bioavailability effect. In addition, good polymeric micelles can prolong the drug circulation time in the human body, reduce the toxicity, and through the EPR effect so as to reach the passive targeting.
The docetaxel micelle which is made by polymer micelles can overcome the drawbacks of commercially available docetaxel agents. However, the research result for the docetaxel micelle lacks of practical value, the major drawbacks include the particle size is too large to play the EPR effect, lower drug loading, the poor stability of the preparation. For example, in Shandong University, KeWei Yu utilizes Pluronic F68 as a micelle carrier, vitamin ETPGS as a solubilizer to encapsulate the docetaxel, such that the average drug loading of the prepared docetaxel micelle only 0.923%. The average particle diameter of the prepared docetaxel micelle is up to 135.1±3.42 nm (Docetaxel polymeric micelles research by KeWei Yu). In Shandong University, Zhai et al utilize TPGS, MPEG-PLA, CSO-SA as a micelles carrier material to obtain the docetaxel micelles, and the drug loading does not exceed 5.2%, the entitled as “a docetaxel mixed micelles and preparation method contained, China patent application No. 201210372072.X).
The freeze-dried powder is an effective way to deposit the drug. The product is dried at low temperatures so that the moisture contained in the product is to be frozen, and then the product is placed in a vacuum environment to be dried, so as to the water is directly sublimed from a solid state to vapor and is excluded from the product, such that the product activity is dried. This method effectively prevents the change of the physicochemical and biological properties of the product, and effectively to protect the stability of the heat-sensitive pharmaceutical active ingredient. The freeze-dried powder in the form of loose after drying, and the colors of the freeze-dried powder basically does not change. The freeze-dried powder can quickly dissolve with water or a hydrophilic organic solvent and restore the physical and chemical properties and biological activity for the original aqueous solution. Because the freeze-dried powder is dried under vacuum conditions, for some easily oxidized substance has a good protective effect. The moisture content of freeze-dried powder product after lyophilization procedure is very low, so that the stability of freeze-dried powder product is increased, and the chance of contamination is to be decreased. Therefore, the preparation method is not only convenient transportation also extended the shelf life of the product.
At present, the research result for the docetaxel freeze-dried powder did not achieve a breakthrough, especially in the components, the particle size after reconstitution and the amount of drug loading and so on. ShouZhu Hao published a method for preparing docetaxel lyophilized powder (the entitled as “A docetaxel pharmaceutical composition, preparation method and use”, China Patent application No. 200780000695.1), and the disclosure of ShouZhu Hao still contains a freeze-dried powder spit temperature 80. Shandong University, Zhang Na et al utilize PLA-PEG copolymer micelles to obtain the docetaxel freeze-dried powder, but the particle size of the docetaxel freeze-dried powder after reconstitution is greater than 200 nm or more (The entitled as “preparation contained docetaxel nanoparticles mixed micelles and the freeze-drying agent”, China Patent application No. 201010151501.1).